Ch 18 Chromosomal and Genetic Syndromes Flashcards
Definition of Neurofibromatosis Type 1
skin and bone abnormalities resulting from tumors growing along the nerves
affects CNS and skin
most common of all types of neurofibromatoses
do not recover from NF1
Neurofibromatosis Type 2
bilateral acoustic schwannomas on the CN 8
meningioma
ependymoma
schwannomatosis
rare form of neurofibromatosis (NF) that causes multiple nerve sheath tumors called schwannomas.
Chronic pain
diagnostic criteria of NF1
6 or more cafe au lait macules
- > 5mm in perpibertal people or >15mm in postpubertal people
- 2+ neurofibromas OR 1 plexiform neurofibroma
- freckling in axilla or groin
- optic glioma
- 2+ lisch nodules
- distinctive bonylesion
- 1st degree relative w/ NF1
neuropathology in NF
- brain tumor
- T2 hyperintensities
- Macrocephaly/megalencephaly - 30-50% of people
neuropathology in NF
- T2 hyperintensities
Seen in what population ? %?
Where does it occur?
T2 hyperintensities
- seen in 60-70% of children
- unidentified bright objects
- occur in basal ganglia, cerebellum, thalamus, brainstem, subcortical WM
- not associated with cognitive impairment
- usually resolve by early adulthood
neuropathology in NF
- Macrocephaly/megalencephaly
Macrocephaly/megalencephaly - 30-50% of people
neuropathology in NF1 - brain tumor What % of people have it? Present by what age What does it involve?
brain tumor
- 15% of people with NF1
- most present by 6 years
- most are benign optic glioma
NF 1 Cognitive impairment
Vs deficits one of the first cognitive deficits 30-65% with LD 30-50% ADHD 4-8% ID language deficits motor skills internalizing mood problems (but not huge risk for severe psych sx) social difficulties
INTACT verbal and visual memory
deficits do not improve over time, but remain consistent or worsen
lifespan with NF1
50-60 years
mortality due to vascular dysplasia
Definition of Tuberous Sclerosis Complex (TSC)
autosomally dominant neurocutaneous disorder genetic disorder that causes tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs arise from one of 2 genes: TSC1 or TSC2 chromosome 9 and 16
Neuropathology of TSC
- cortical tuber
- subependymal nodules
- subependymal giant cell astrocytoma
Cortical tuber
potato like appearance of lesions
proliferation of glial and neuronal cells
loss of six layered structure of cortex
Subependymal nodules
form in walls of ventricles
may become subependymal giant cell astrocytoma (SEGA)
subependymal giant cell astrocytoma (SEGA)
- slow glowing tumor
- seen in children developed under 20 years
- 5-20% of children
Dx/ problems associated with TSC
80-90% with epilepsy - begins in infancy, often intractible
45% ID
40-50% ASD
25-50% ADHD
increased risk for anxiety and depression
>50% behavioral problems (aggressive outburst, temper problems)
TAND
Life expectancy of TSC
depends on severity of symptoms
Treatment of TSC
no cure
use antiepiletic drugs for seizures
Everolimus (mTOR inhibitor) to tx SEGA and epilepsy
not good candidates for surgery because have multiple seizure foci
NP results for TSC
bimodal distribution of IQ (30% of profound ID, 70% near normal - 130)
LD in normal IQ
attention and EF deficits
memory recall deficit, recognition intact
TAND - Tuberous sclerosis associated neuropsychiatric disorders (psychsocial behavioral intellectual problems)
What is TAND
tuberous sclerosis associated neuropsychiatric disorder
Sturge Weber Syndrome (SWS)
neurocutaneous disorder
PFVG port wine birthmark (PWB) facial capillary malformation - usually affects face in region of ophthalmic division of trigeminal nerve vascular malformation of the brain glaucoma
Gene location of SWS
somatic mosaic mutation in the GNAQ gene on 9q21
neuropathology of SWS
leptomeningeal angioma
cerebral atrophy
cortical calcification
leptomeningeal angioma
- capillary venous vascular malformation of the brain
- port wine birthmark increases brain involvement by 10-20%
- bigger size birthmark increases risk
cerebral atrophy and cortical calcification in Sturge Weber syndrome
- where is it usually seen?
- one other characteristic
usually lateralized
seen in occipitoparietal regions
disorders and medical problems with SWS
seizures (typically begin in childhood)
- 75% unilateral brain involvement have seizures
- 95% bilateral brain involvement have seizures
- seizures occur on the side of body contralateral of PWB
headaches and migraines
stroke like weakness contralateral of brain involvement
CNS problems when PWB involves upper division of trigeminal nerve
30-60% glaucoma
growth hormone deficiency 18x more likely
early onset dementia in 50s and 60s
Kids with SWS are more vulnerable to stroke like episodes precipitated by?
falls
Prognosis of SWS can be related to
age of onset of seizures
- onset before age 6 months has worse prognosis
- later seizure onset (after 9-12 mos), unilateral brain involvement usually have better outcome
Treatment of SWS
no cure
use of antileptic drugs to control seizurs
surgery (surgical lobectomy, hemispherectomy, callosotomy)
low dose aspirin (microvascular thrombosis)
NP results for SWS
few studies done with this population, no typical NP profile
60% with ID - LOW IQ!!
Learning problems
attention
processing speed slow
sensorimotor functions vary, and seen in stroke-like episodes
Vs skills also deficits
language comprehension, word list, verbal memory (L hemisphere)
disruptive behavior in children
anxiety in children
SUDs and depression in adults
Williams Syndome
facial dysmorphology (ELF - like!!)
connective tissue abnormality
cardiovascular disease
mild to mod cognitive deficits
Gene location of Williams syndrome
deletion of 26 to 28 genes on chromosome 7
neuropathology of Williams syndrome
reduction of cerebral volume with preservation of cerebellar volume (gray matter ok, reduced WM)
narrowing of corpus callosum
abnormal cell density in primary visual cortex
reduced sulcal depth in intraparietal occipitoparietal sulcus (VS deficits!)
abnormal neural pathway, amgydala activation when seeing threatening scenes and under activation when seeing threatening face
- hypersocial and anxious trait
medical disorders seen in Williams (5)
70% failure to thrive as infants
- motor delay and hypotonia as babies
atypical language development in sequence
50-75% cardiovascular disease - accounts for shortened lifespan
50% strabismus, cataracts, visual acuity problems
85-95% hypersensitivity to sounds
NP results in Williams
average IQ = 55 (most of them are ID) verbal IQ > non verbal IQ VS deficit - HALLMARK!! object and facial recognition in tact 50-60% ADHD hypersocial, hyperfriendly, lack social judgment anxiety conversation sterotypies (open ended social situations ok, but no good in constrained social contexts)
Interesting characteristics about williams
Elf like
musical affinity
premature gray hair and wrinkling of skin
hoarse voice
22q11.s deletion syndrome AKA
DiGeorge syndrome
Shprintzen syndrome
Velocardio facial syndrome
22q11s deletion syndrome definition
multiple congenital anomalies
cardiac malformations
hypocalcemia
hearing loss (conductive)
palatal deficits
neuropathology of 22q11s
reduced total brain volume by 10% (white matter more reduced than gray matter)
frontal lobe volume ok
reduced parietal lobe volume
reduced cerebellar volume (vermis and pons)
reduced hippocampus
disorganized axonal tracts
cortical thinning in parietooccipital and orbitofrontal regions
other medical disorders in 22q11s
Medical
75-80% congenital heart defect - leads to mortality
69% palatal abnormality in speech and feeding
NP
82-100% LD
30-40% ADHD
10-30% ASD
Mood
30-40% anxiety, phobia, separation anxiety, OCD
20-30% mood disorders (MDD and Bipolar)
25-30% psychotic disorder
22q11s NP results
nonverbal before age 3
expressive < receptive language
IQ borderline
verbal > non verbal skills
NLD profile deficits in facial memory math difficulties (VS based only)
impaired attention and EF
strong rote memory
good decoding
22q11s has increased risk for
psychosis and schizophrenia (25x general population)
- onset late teens to early 20s
- does not respond well to antipsychotic meds
interesting things about 22q11s
bland affect
no facial expression
Adrenoleukodystrophy (ALD)
X linked
recessive disorder affecting CNS myelin and adrenal cortex caused by defect in gene ABCD 1
degenerative
death within 2-5 years after onset
males or females more likely to have ALD?
males, because x-linked disorder
ALD neuropathology
inflammatory brain demyelination - posterior pattern in 80%, demyelination at corpus callosum, spread into parieto-occipital white matter
noninflammatory distal axonopathy - long tracts of spinal cord, AMN phenotype
4 main phenotypes of ALD
cerebral inflammatory - childhood cerebral (CCALD) - CLASSIC TYPE 31-35% - adolescent (AdolCALD) - adult AMN (adult onst) - AMN no cerebral: slow progression - AMN cerebral: rapid progression Addison asymptomatic
CCALD onset features and age
3-8 years
first presenting like ADHD symptoms
then intellectual, behavioral, neurological declines
minimally responsive state within 2 years of onset, then DIE!!!
AdolCALD
progression slower than CCALD adrenal insufficiency neurological dysfx psych sx death within 1-2 years of onset
ACALD
early cognitive decline
psych sx e.g. schizophrenia or psychosis
motor impairment
death within 3-4 years of onset
Treatment of ALD
adrenal hormone replacement therapy to treat primary adrenocortical insufficiency
Lorenzo’s oil
hematopoietic stem cell transplant (HSTC)
- leads to improvement in nonverbal IQ
- good outcome
STEM cell - 68% 5-year survival rate from related donor
NP results for ALD
non verbal deficits (VS)
EF deficits
attention problems seen in children first
psych sx seen in adults first
pattern seen in other demyelinating diseases such as MS
Klinefelter syndrome 47 XXY
most common sex chromosome aneuploidy ONLY in men extra X chromosome tall stature hypogonadism fertility problems
Kleinfelter Diagnosis when?
10% prenatally, 25% childhood, 65% puberty
neuropathology of klinefelter
reduced overall brain volume (limbic area, caudate nucleus, cerebellum)
enlarged ventricles
reduced temporal lobe gray matter volume
increased anomalous cerebral dominance (right ear advantage)
language less lateralized in men (more activity in R)
Disorders in klienfelter
35-65% ADHD 5-10% ASD 50-75% LD mortality rate, loss of 2.1 years increased rate for breast CA
progression of Klinefelter
subtle in childhood, children with motor and speech delay
tall stature seen in adolescence usually
testosterone deficiency in puberty - slow pubertal development
no facial, pubic hair
microorchidism - SMALL testes
large breasts
Treatment of Klinefelter
Testosterone replacement therapy TRT
NP profile in Klinefelter
IQ generally average nonverbal > verbal language skills deficit dyslexia ADHD, more I than C slow processing sensorimotor deficits anxiety, depression, social withdrawal, behavioral shy, emotionally sensitive, socially immature
Fragile X syndrome
repetition in CGG trinucleotide sequence at Xq27.3
leading cause of inherited ID
most common single gene disorder leading to ASD!
normal lifespan
Male or female more frequent in Fragile X
Males more affected
Neuropathology of Fragile X
enlarged hippocampus, caudate nucleus, thalamus, amygdala (increased ASD and stereotypic tendencies)
reduction in size of cerebellar vermis
dysmorphia of cerebellar vermis and caudate nucleus (predict lower IQ)
medical disorders with Fragile X
10-20% epilepsy mostly in males
- rhythmic theta waves, decreased and slower alpha
waves, slower background activity
- seizures usually resolve by adolescence
fragile X associated tremor/ataxia syndrome (FXTAS)
- progressive gait ataxia, intention tremor, parkinsonism
peripheral neuropathy, STM loss, EF
25-57% ASD in males
ADHD in 70-90% males, 30-50% females
80% males ID, 30% females ID (males lower IQ)
progression of Fragile X
developmental delays first sign
large testicles during puberty
normal fertility
Treatment of Fragile X
no cure
drugs that target glutamate receptors and GABA receptors
NP results of Fragile X
ASD ADHD ID (males worse, females mild) poor math VS speech is echolalic, palilalia, perseveration, poor articulation, stutter hyperarousal, approach withdrawal social behavior poor eye contact (ASD Stuff) EF, attention, processing speed
Fragile X physical characteristics
prominent ears hyperextensive joints flat feet soft skin macroorchidism long face
Turner Synrdome
results from missing or abnormal second X chromosome only in females short stature webbed neck Cardiovascular malformation congenital heart disease kidney malformation
neuropathology of Turner syndrome
decreased volume of parietal and occipital cortices
abnormal structure and function of amygdala, insula, anterior cingulate, ventromedial prefrontal cortices, orbitofrontal cortex
dysfunctional frontoparietal circuitry
agenesis or anatomical differences of corpus callosum
medical disorders of Turner syndrome
17-45% cardiovascular malformation short stature osteoporosis, infertile 30% thyroid (hypothyroidism) 25% ADHD 45-55% math disability reduced life expectancy due to cardiovascular malformation
progression and presentation of Turner
developmental motor delays early
mosaicism (genetically different set of cells in body)
treatment of Turner
estrogen, progesterone (growth hormone therapy)
NP results of Turner Syndrome
ADHD NLD (spatial, math) *nonverbal deficits* social skills average IQ significant verbal > non verbal motor deficits social cognition (socially immature, lack connectedness)
Phenylketonuria (PKU)
mutation from PAH gene
identified through newborn screening blood test
autosomal recessive disorder
classified based on Phe level at dx
most people have mild phenotype
A birth defect that causes an amino acid called phenylalanine to build up in the body.
Treatment of PKU
Phe-restricted diet
no cure
Neuropathology of untreated PKU
hypomyelination and gliosis
progressive white matter degeneration
delay in development of cerebral cortex
diffuse cortical atrophy and reduced dendritic arborization
Treated neuropathology of PKU
white matter abnormalities (t2 hyperintensity)
volume loss in cerebrum, corpus callosum, hippocampus, pons
medical disorders with PKU
75% untreated have neurological dysfunction
5% of untreated have supranuclear motor disturbance
13-46% ADHD I
normal lifespan
presentation of PKU
untreated infants and babies - hypotonia, irritability, feeding problems, musty odor, psychomotor retardation seizures in untreated babies 4-6 mos cognitive decline 3-4 years beh problems OCD, self injury, tactile sensitivity IQ below 50 if untreated
important fact about PKU
early treatment makes a big difference
NP results of PKU
untreated IQ < 50 treated IQ normal math problems reading writing ok VS deficits EF deficits processing speed related to PKU phenotype but not phe levels adhd
Prader Willi Syndrome
lack of paternally expressed genes in q11-13 region of chromosome 15
Hallmark of Prader Willi
hyperphagia - EXCESSIVE EATING hypotonia hypogonadism - not enough sex hormones obesity mild to mod ID
Neuropathology of Prader Willi
structural neuroanatomical abnormality (pituitary gland, periventricular nucleus of hypothalamus…)
connectivity abnormality (FA studies, high trace value in left frontal white matter, left dorsomedial thalamus; low FA in posterior internal capsule, right frontal WM, corpus callosum)
abnormality in brain region related to eating (differences in amygdala and orbitofrontal cortex, delayed response to glucose ingestion in areas of satiety)
medical disorders in Prader Willi Syndrome
IQ mild to mod ID
25% ASD
hypotonia life long
hypogonadism both male and female
lung disease, OSA, decrease O2 saturation
gastrointestinal complications (decreased saliva production, swallowing difficulties, unable to vomit)
obesity
short stature
diminished life span due to respiratory failure, choking
presentation and course of prader willi syndrome
2 clinical phases
- neonatal (birth to 3), hypotonia, hypereflexia, feeding problems, failure to thrive, delayed milestone, language
- hyperphagic (onset 2-6 yrs), constant need for food
Treatment for prader willi syndrome
no cure
early dx and intervention for dietary and behavioral problems
growth hormone tx
intervention on food restriction
SSRI for compulsive and injurious behavior
NP results in Prader Willis syndrome
IQ mild to mod ID ASD poor adaptive fx non verbal IQ> verbal IQ OCD, ritualistic tendencies behavior problems social deficits psych (bipolar, mood)
Angelman Syndrome
lack of maternally expressed genes in q11-q13 region of chromosome 15 severe ID ataxia epilepsy severe speech and language delays repetitive, stereotyped behaviors sensory seeking happy and inappropriate laughter hand flapping, waving (motor stereotypies)
neuropathology of angelman syndrome
usually normal brain structure
EEG pattern
- symmetrical high voltage slow wave activity not associated with drowsiness
- very large amplitude slow activity in runs and more prominent in frontal region
- spike and sharp waves seen posteriorly and provoked by eye closure
background rhythm in ages 10+ slower than normal, focal spikes and intermittent and continuous triphasic delta activity over frontal region
medical problems in Angelman syndrome
80-90% epilepsy
- tonic clonic, absence, complex partial, myoclonic, atonic, and tonic seizures
100% movement or balance disorder with ataxia of gait and tremulous limb movement
100% severe developmental delay, esp language and speech
sleep disorders
life span normal
presentation and course in angelman syndrome
dev delay first noted in 6 months
slow progression
seizure onset 1-5 years, diminish during late childhood and adolescence and return in adulthood
treatment of Angelman
no cure
multiple AED
speech therapy, use communicative device
NP results in angelman syndrome
IMPAIRMENT in speech (absent or few words)
SEVERE ID
short attention span
movement disorder
abnormal muscle tone
behavioral WEIRD! (laughter inappropriate, smile, hand flaps, hypermotoric)
good eye contact, social skills ok
severe seizure cause temper tantrums, irritability
palilalia
repetition of one’s own words
phexiform neurofibroma
large, non encapsulated tumor that diffusely involves long nerve segments and has increased of becoming malignant
schwannoma
benign nerve sheath tumor composed of schwann cells
schwann cells
produce myelin sheath covering peripheral nerves
karyotype
number and appearance of chromosome
hamartoma
benign, focal malformation of tissue that has developed in a disorganized manner
gynecomastia
male breast enlargement
aneuploidy
abnormal no of chromosomes
de novo mutation
genetic mutation that is present for the first time in a family member and not passed down by either parent
ependymoma
tumor arising from ependyma
ependyma
membrane lining the ventricular system
glioma
tumor arising from glial cells in brain or spine
facial features of angelman
wide mouth protruding tongue
deep set eyes
prominent chin
